Dialysis – from hate to hope?

By Matt Brady and Mark Varley

Renal disease is an extremely important target for effective medical treatment. It affects 26 million adults1 in the US, and every year nearly 50,000 Americans die from the condition – more than from breast (41,000) or prostate (28,000) cancer. The regular form of treatment is dialysis, first developed in 1943, which is a procedure for cleaning the blood when the kidneys stop functioning effectively - most commonly by haemodialysis which circulates the patient’s blood through a machine with a special filter called a dialyser. Whilst both the process and the equipment have seen significant enhancements over the years, kidney transplantation still has a substantial lead in terms of both survival rates2 and quality of life.

The key aims of nephrologists (specialist doctors who treat kidney diseases) are to manage chronic kidney disease to prolong kidney function for as long as possible; and secondly, only once the disease has progressed to end stage renal disease (ESRD), provide renal replacement therapy (RRT) until a suitable donor kidney can be found3. This clear priority order arises because RRT, which currently comprises a range of dialysis techniques, falls a distant second to a functioning human kidney in terms of both quality of life and long term patient outcomes.

From a patient perspective, haemodialysis (HD) considerably affects quality of life, not only due to the time spent on dialysis three times a week (including travel for the vast majority who are treated in dialysis centres), but also feeling ill before, during and after any given treatment session. Further lifestyle limitations include a constant requirement for close control of diet and fluid intake. These considerations help explain why the leading internet forum4 for the patients who benefit from this miraculous, life-saving treatment is called www.ihatedialysis.com.

Yet as dialysis remains the main form of therapy for those with this serious condition, how can the impact on patients’ lives be improved?

Recent evidence suggests that haemodialysis in the home setting, where feasible, can bring both reduced lifestyle impacts and improved outcomes – especially where it enables more frequent dialysis, widely believed to provide better results. Accordingly, this option is now becoming supported or encouraged by payers5. Based around this trend, recent and new market entrants6 are already offering more streamlined, ’user-friendly’ equipment for home use, seeking to unlock the potential for more frequent home treatment. Doubtless the major market players will also be investing R&D dollars in this space.

So, what other improvements can we hope to see in the management of kidney disease for the future?

A good place to start is the way in which the patient and his/her disease are managed by the nephrologist. An important recent trend is the effort to educate general practice in making timely referrals so active management can begin earlier – with the promise of significant positive impacts, such as reduced patient mortality, or an increased likelihood of receiving a transplant7.

In the medium term, the wearable artificial kidney (WAK8) offers a vision where HD becomes continuous – with potential benefits including reduced lifestyle impact (including lifted dietary restrictions and ambulation during treatment), reduced cardiovascular stress, and elimination of inter-treatment toxin build-up. The current prototype, which leverages the miniaturisation possibilities offered by use of lower flow rates over longer periods, is a 10 -pound device which has already demonstrated promising results in an FDA-approved proof-of-concept trial9. Future prototypes are expected to be even smaller.

Projecting this further into the future, it’s tempting to imagine artificial kidney technology becoming sufficiently miniaturised that it could be implanted into the patient. However this would require a fundamental change in the HD operating principle of transferring toxins and excess fluids into a secondary dialysate circuit – and at this point we are not aware of any proposed mechanisms which would allow this using conventional micro-fluidic technology.

Tissue engineering: improving incidence of kidney transplant

Whilst both quality of life and outcomes are in general significantly better following kidney transplant than on RRT, unfortunately demand significantly outstrips supply: out of the 100,000 or so people waiting for a kidney transplant in the US, each year only 17,000 actually receive one10. Of these 7% of transplants fail within one year, 17% after three years and 46% after ten years. In reality over 20% of kidney transplants each year are re-transplants.

Around a quarter of kidney transplants are from a living donor11 – and this figure would doubtless be many times higher if willingness on the part of potential donors were the only limitation. There is a long list of factors which contribute to the suitability of a given donor kidney for a particular patient, which severely limits the number of matches which can be made. The more conditions are met, the more successful a transplant is likely to be. Conversely, if too few conditions are met, a transplant cannot go ahead at all.

These considerations have driven considerable research and development in tissue engineering of kidneys: the attempt to ‘grow’ a new organ within a laboratory setting, ready to be implanted into the patient. There are three main strategies currently being seriously considered:

Self-assembling stem cells – extracting stem cells from the patient and causing them to differentiate and self-assemble into kidney-like structures. These could then be implanted near the damaged kidney and connected to the existing renal blood supply and ureter. Due to the perfect tissue match which should result, the body should naturally integrate these structures, so replacing lost kidney function.

Decellularization – by removing the cells from a non-matched donor kidney, the complex kidney architecture can be preserved. It’s hoped that such a structure could be re-filled with cells from the patient, so creating a new kidney with an exact tissue match and effectively zero risk of acute immune rejection upon implantation.

3D printed scaffolds – creating an artificial structure which can then be colonised by the patient’s cells. In this concept the scaffold can potentially be allowed to dissolve over time, as the structure is replaced by genuine tissues.

Of these, the 3D printed scaffolds is the furthest away in development terms: due to the incredible complexity of the kidney, replicating the structure, signalling proteins and cellular niche is exceptionally difficult and unlikely to be possible even given foreseeable short to medium-term developments in 3D printing technology. The technique most likely to form a viable tissue-engineered kidney is decellularization – yet even this most promising solution is estimated at 20 -50 years in the future, with early animal models still being developed and clinical trials a pipe dream for now.

Bridging the gap: disruptive possibilities

Perhaps combining the best of conventional technology with the best of biological science might generate a disruptive technology far sooner.

A bio-artificial kidney12, consisting of thousands of microscopic filters and a bioreactor containing patient liver cells to replicate the metabolic and water balancing roles of the kidney. This would be implanted into the patient and function 24 hours a day using the patient’s own blood pressure to filter the blood. Proof of concept has been carried out and clinical trials will hopefully start this decade.

Organs harvested from human-animal chimera13 – an idea which has existed for decades but which is currently seeing spectacular progress following the discovery of CRISPR/CAS9 genome editing. Issues remain – from the risk of the unintended introduction of ‘human-like’ cognitive changes to the chimera, to the risk of porcine material in the organ causing rejection. However the promise of biologically-grown organ with a perfect genetic match for the patient is hard to ignore.

Meanwhile for us the message is clear: this is a sector where there is an urgent need for innovation, and where several potentially-feasible pathways to radical and market-disrupting products have already been proposed. Today’s big industry players (both equipment suppliers and service providers) will need to monitor these developments closely, and ensure they are in a position to benefit from them as they advance – or risk obsolescence tomorrow. The best way to stay on board is likely to be by stepping into the innovation driving seat now: as Lincoln is often quoted, the best way to predict the future is to create it.

The real payoff, though, has to be the transformation of millions of lives promised by these innovations.

1https://www.kidney.org/2See, for example, ERA-EDTA Registry Annual Report 2013 which shows 5-year survival rates for the 2004-2008 cohort of around 82% for transplant, versus around 53% for dialysis.3Kidney transplantation is sometimes also considered under the RRT heading, especially in the context of outcome comparisons with the various forms of dialysis.4At time of writing, more than 10,000 members and over half a million posts since 2005. The forum’s strap line is “We are not being negative, we just hate dialysis.”5Ibid6E.g. NxStage and Quanta FS7Timing of referral of chronic kidney disease patients to nephrology services (adult) – Nephrology 2010; 15, S2-S118http://www.wakfund.org/, wearable HD endeavours also underway at AWAK / Neokidney9http://www.NephrologyNews.com, November 201510https://www.kidney.org/11ERA-EDTA Registry Annual Report 201312http://pharm.ucsf.edu/kidney13http://www.theguardian.com/commentisfree/2016/jun/06/pig-human-embryos-scare-stories-stem-cells-organs

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